Infection by Leishmania braziliensis is the major cause of American cutaneous leishmaniasis (ACL) in Brazil. Although T-cell cytokines are critical determinants of the outcome of infection in mouse models of leishmaniasis, little is known about the role of these cytokines in the human disease. The goal of this proposal is to learn about the role of T-cells and cytokines in the immunopathogenesis of ACL. We will compare the immune response at the site of disease in patients with localized cutaneous leishmaniasis (LCL), the self-healing form of the disease, to those with mucocutaneous leishmaniasis (MCL) a progressive destructive manifestation of infection. These immune responses will be compared to that of Montenegro reactions, the standard measure of delayed-type hypersensitivity in these patients. In the first aim, we propose to measure the T-cell cytokine pattern in lesions of the different clinical forms of ACL as caused by L. braziliensis infection. Our preliminary data suggest that IFN-gamma is characteristic of most LCL lesions. A mixture of IFN-gamma and IL-4 is present in MCL lesions. We expect to determine if subgroups of LCL patients express IL-4 in lesions. These patients may be at risk for developing MCL. The second aim is designed to identify the subsets of T cells responsible for the local cytokine patterns. We plan to investigate the functional role of CD4+, CD8+, gamma/delta+ and CD1-restricted T cells in the local immune response. The antigen presentation element will be investigated and preliminary studies will be conducted to study the antigens recognized by these cells. Finally, the third aim will elucidate the role of IL-12 in influencing the local cytokine pattern in terms of proliferation and cytokine release by the various T-cell subsets. These studies will expand our knowledge of the human immune response to infection and provide new targets for immunotherapeutic intervention in leishmaniasis and other parasitic infections.